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1071-412X/02/$04.00⫹0 DOI: 10.1128/CDLI.9.2.207–215.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.


Role of Infectious and Immune Factors in Coronary and

Cerebrovascular Arteriosclerosis
Claudia Stöllberger1* and Josef Finsterer2
Second Medical Department, Krankenanstalt Rudolfstiftung,1 and Neurologisches Krankenhaus Rosenhügel,2
A-1130 Vienna, Austria

Arteriosclerosis is the main cause of coronary heart and BACTERIAL AND VIRAL INFECTIONS AND
cerebrovascular disease which, in turn, are the most common ARTERIOSCLEROSIS
causes of death in the industrialized world. An acute event in
Infectious pathogens. (i) Helicobacter pylori. H. pylori is a
coronary heart or cerebrovascular disease is typically precipi-
gram-negative spiral bacterium and the main etiological factor
tated by thrombosis occurring at the site of arteriosclerotic
in gastritis and peptic ulcer disease. H. pylori infection is pos-
plaque disruption. Arteriosclerotic plaques consist of a fibrous
tulated to have an effect on clotting mechanisms (47). A fur-
cap overlying a lipid-rich core. Many cell types are involved in
ther hypothesis suggests that exposure to H. pylori may lead to
their formation, including platelets, endothelial cells, activated
an increased risk of arteriosclerosis by an autoimmune process
monocytes, macrophages derived from monocytes, and smooth
to heat shock proteins (Hsps). Seroepidemiological studies
muscle cells. Macrophages and T lymphocytes are critical in
about the role of H. pylori in the development of coronary and
the growth and change of plaques through the secretion of
cerebrovascular arteriosclerosis yielded controversial results.
growth factors, which stimulate smooth-muscle proliferation
and extracellular matrix secretion, cytokines such as gamma Several authors found an association (41, 46, 64, 79; M. Jan-
interferon (IFN-␥) and interleukin-1 (IL-1), and extracellular kovic, A. Hirschl, S. Guber, M. Kundi, and W. Lalouschek,
matrix-digesting enzymes such as metalloproteinases, which Abstr., Cerebrovasc. Dis. 11:106, 2001), whereas others did not
weaken fibrous caps. (16, 26, 29, 47, 77). Further studies found an association, ad-
The currently accepted hypothesis is that arteriosclerosis equately explained by the much stronger association of H.
develops as a response to injury and that it is primarily a pylori infection with age, male gender, and social class, which
chronic inflammatory condition. Infections have long been are linked with coronary heart disease (68, 87, 95). In a study
postulated to play an important role in the etiology of arterio- of socioeconomically homogeneous men, controlled for age
sclerosis. Two patterns of association have emerged: a link and smoking, limited evidence of association between H. pylori
between chronic low-grade inflammation or infection and the exposure and risk for future myocardial infarction was found
slow process of arteriosclerosis and an association between an (82). A population-based study did not find an association of
acute systemic inflammatory response and a transiently in- elevated H. pylori antibodies with ischemic stroke; however, H.
creased risk of an acute cardiovascular event. pylori infection was associated with strokes caused by small-
New interest in the role of infections and inflammatory artery occlusion (39). To explain the contradictory results re-
mechanisms for the pathogenesis of coronary and cerebral garding the association of H. pylori with arteriosclerosis, it was
artery diseases is based on the results of seroepidemiologic suggested that strains expressing the virulent cytotoxin-associ-
studies, studies about inflammatory mediators and endothelial ated gene product A (CagA) are more strongly related to
dysfunction, and recent studies evaluating the role of antibiotic coronary heart disease than are other strains of H. pylori (51).
therapy in arteriosclerosis. The present report reviews the cur- A study in late-middle-aged men, however, showed that CagA-
rent status of knowledge regarding the role of different infec- positive strains appear to be no more strongly related to the
tious agents and of inflammatory and immune mediators in the disease than other strains (101).
pathogenesis of coronary and cerebral artery disease and dis- (ii) Chlamydia pneumoniae. C. pneumoniae is a gram-nega-
cusses the possible implications of these mechanisms with re- tive intracellular bacterium. An association of coronary heart
gard to diagnosis and therapy. We do not discuss the complex disease and infections with C. pneumoniae, an important re-
entity of vasculopathies of different causes, including cardiac spiratory pathogen, has been initially found by seroepidemio-
allograft vasculopathy, but restrict this review to arteriosclero- logic studies (88). The presence of C. pneumoniae has been
sis. shown in atheromatous plaques of coronary and carotid arter-
ies (14, 104). An immune reaction to chlamydial Hsp60 has
been shown in coronary atheroma tissue, especially in macro-
phages and foam cells (2). In human carotid artery plaques, C.
pneumoniae-reactive T lymphocytes have been identified (71).
* Corresponding author. Mailing address: Steingasse 31/18, 1030
Vienna, Austria. Phone: 43-1-713-98-70. Fax: 43-1-713-98-70. E-mail: In an autopsy study, examining coronary artery specimens, it
claudia.stoellberger@chello.at. has been found that intracellular infection with C. pneumoniae


relates to the severity of arteriosclerosis, whereas serum anti- endothelial cells may increase cellular proliferation and inhibit
body titers did not (25). apoptosis of infected smooth-muscle cells, thereby contribut-
Seroepidemiological studies of the role of C. pneumoniae in ing to an increase in the mass of arteriosclerotic lesions. Fur-
the development of coronary and cerebrovascular arterioscle- thermore, individuals infected with CMV have impaired endo-
rosis yielded controversial results. Several authors found an thelium-mediated coronary vasodilator responses (24). Herpes
association (15, 26, 27, 77, 85, 91, 93; Jankovic et al., Cerebro- simplex virus types 1 and 2 have been found in human arte-
vasc. Dis. 11:106), whereas others did not (16, 19, 39, 41, 42, 61, riosclerotic lesions (5).
63, 83, 95, 100). The main explanations for these controversial Seroepidemiological studies of the role of CMV and herpes
findings are that the studies were done in different populations, simplex virus types 1 and 2 in the development of coronary and
used different criteria for controls, were adjusted for potential cerebrovascular arteriosclerosis have yielded controversial re-
confounders to different degrees, and were, therefore, prone to sults. Several authors found an association (10, 26, 73, 85, 93;
different biases. Furthermore, most of these seroepidemiologi- Jankovic et al., Cerebrovasc. Dis. 11:106), whereas others did
cal studies detected C. pneumoniae antibodies by microimmu- not (16, 27, 41, 64, 98). These conflicting data are again ex-
nofluorescence, a method with inherent diagnostic problems plained by methodological causes (17). Furthermore, individ-
(17). Although there are many indicators, no definite proof ual and gender differences in the host response to CMV might
exists that the presence of C. pneumoniae causes either initia- account for the disparate results. Two studies in patients un-
tion of arteriosclerosis or activation of an arteriosclerotic dergoing coronary angiography have shown that CMV elicits a
plaque. subclinical inflammatory response, but only in certain individ-
A further possible role of C. pneumoniae in the pathogenesis uals, and that individuals with an inflammatory response ap-
of arteriosclerosis could be that chronic or acute chlamydial pear to be susceptible to the atherogenic effects of CMV,
infection anywhere in the body activates arteriosclerotic whereas those without such a response appear to be resistant
plaques. An association between immunoglobulin A (IgA), but (9, 107). Postulating that sex might have an effect on patterns
not IgG, antibodies to C. pneumoniae and the subsequent risk of inflammatory and immune responses to CMV infection, a
of death from ischemic heart disease, the risk of ischemic study in patients evaluated for coronary artery disease found
stroke, and the severity of arteriosclerosis of carotid or femoral that, in men, CMV appears to contribute to coronary artery
arteries has been found (23, 64, 96). In patients undergoing disease risk, insofar as it predisposes to inflammation. In
carotid endarterectomy, the plaques were investigated for C. women, other mechanisms, possibly related to the type of im-
pneumoniae and the blood was examined for antichlamydial mune response generated by the host, appear to be responsible
antibodies. Associated with symptomatic disease was a high- for the proatherogenic effects of CMV (109).
level of antichlamydial IgA, whereas no association between C. (v) HAV. Hypothesizing that intracellular pathogens associ-
pneumoniae presence in the plaque and symptomatic disease ated with a persistent antibody response may contribute to
could be detected (52). arteriosclerosis, the authors of one study selected hepatitis A
Furthermore, there are indications that seropositivity for virus (HAV) as a candidate pathogen for a serologic examina-
C. pneumoniae might enhance the atherogenic effects of tion of patients undergoing coronary angiography. In this
other vascular injuries. A case-control study suggests that study, HAV seropositivity was an independent predictor of risk
the proatherogenic effects of lipoprotein may be enhanced or for coronary artery disease and elevated CRP levels (106).
partly mediated through the formation of circulating immune (vi) HIV. The common cardiac manifestations in patients
complexes containing C. pneumoniae-specific IgG antibodies with AIDS are pericardial effusion, myocarditis, dilated cardio-
(32). The simultaneous presence of high levels of antibodies to myopathy, endocarditis, pulmonary hypertension, malignant
C. pneumoniae and of antibodies to human Hsp60 have been neoplasms, and drug-related cardiotoxicity. However, there
found to substantially increase the risk for coronary arterio- have been some reports of acute coronary thrombotic events in
sclerosis (11). patients infected with human immunodeficiency virus (HIV).
(iii) Microorganisms associated with periodontitis. Dental One or more atherosclerotic plaques within carotid arteries
infections appear as cardiovascular risk factors in some cross- were found in a large proportion of middle-aged HIV-positive
sectional studies and in follow-up studies, and the association individuals. The presence of arteriosclerosis within this popu-
is independent of the “classic” coronary risk factors (4, 62). It lation was not associated with the use of protease inhibitors but
is hypothesized that this association may be due to an under- rather with “classic” cardiovascular risk factors such as smok-
lying inflammatory response trait, which places an individual at ing and hyperlipidemia, which are amenable to interventions
high risk for developing both periodontal disease and arterio- (20). Autopsy studies in HIV-positive children and young
sclerosis. Furthermore, periodontal disease might provide a adults suggest the presence of an underlying arteriopathy. A
biological burden of inflammatory cytokines that promote ar- recent study demonstrated that the HIV envelope protein,
teriosclerosis and thromboembolic events. In an in vitro model gp120, activates human arterial smooth-muscle cells to express
of thrombosis, platelet aggregation-associated protein has tissue factor, the initiator of the coagulation cascade. The
been found to be expressed on Streptococcus sanguis and on activation of smooth muscle cells by gp120 may play an impor-
Porphyromonas gingivalis, both of which are involved in peri- tant role in the vascular, thrombotic, and inflammatory re-
odontitis (38). Further data and prospective studies are needed sponses to HIV infection (89).
to assess the role of dental infections in the pathogenesis of Infectious burden. Most of the published studies thus far
arteriosclerosis. have investigated the association of only one microorganism
(iv) CMV and herpes simplex virus. Cytomegalovirus with arteriosclerosis. The number of different pathogens to
(CMV) is the largest of the herpesviruses. CMV infection of which an individual has been exposed, i.e., the“infectious bur-
VOL. 9, 2002 MINIREVIEWS 209

den”, possibly may have an influence on the development of infections. One study in the general British male population
arteriosclerosis. Only a few studies have investigated the im- found that baseline values of CRP were associated with future
pact of viral and bacterial infectious burdens. One study in 120 risk of coronary heart disease, but no strong associations of
post-myocardial infarction patients ⱕ50 years in age found CRP with H. pylori seropositivity or C. pneumoniae IgG titers
that, after adjustment for coronary risk factors and socioeco- were observed (18). Similar findings were reported in a study
nomic status, the combination of seropositivity to both C. pneu- on patients with acute coronary syndromes (16). In another
moniae and CMV infection was associated with an increased prospective follow-up study in patients with coronary heart
inflammatory response and a markedly increased risk of pre- disease, the combination of CMV seropositivity and elevated
mature myocardial infarction (30). In 105 patients with tran- CRP levels was identified as a strong, independent predictor of
sient ischemic attacks or minor stroke, combined seropositivity mortality (73).
to C. pneumoniae, H. pylori, and CMV lead to an elevated risk It remains uncertain whether CRP is an independent risk
ratio (Jankovic et al., Abstr., Cerebrovasc. Dis. 11:106). In a factor for coronary heart and cerebrovascular arteriosclerosis.
coronary heart disease primary prevention trial, high levels of First, in many studies, the associations weakened after baseline
antibody to either herpes simplex virus type 1 or C. pneu- confounding factors were adjusted for (18). Second, no direct
moniae indicated increased the risk for coronary events inde- evidence exists showing that CRP directly contributes to vas-
pendently of the other, and their joint effect was close to cular damage.
additive (85). One prospective study in 1,018 patients with (ii) Fibrinogen. Plasma fibrinogen is an acute-phase protein
angiographically documented coronary artery disease evalu- and a hemostatic factor. In a cross-sectional study including
ated the effect of eight infectious pathogens (herpes simplex men, participants with prevalent coronary heart disease had
virus types 1 and 2, CMV, Epstein-Barr virus, Haemophilus markedly higher fibrinogen levels than participants without
influenzae, C. pneumoniae, Mycoplasma pneumoniae, and H. coronary heart disease. The associations weakened after fur-
pylori) on the risk for cardiac death. Seropositivities to Epstein- ther adjustment for central obesity (45). In a study on patients
Barr virus, H. pylori, and herpes simplex virus type 2 were with stable angina pectoris, the level of fibrinogen in serum was
independently associated with cardiac death. An increasing an independent predictor of cardiovascular death, nonfatal
number of pathogen burden was significantly predictive of the myocardial infarction, and the risk of revascularization (37). In
long-term prognosis. Seropositivities from 0 to 3, 4 to 5, and 6 contrast, in patients with acute coronary syndromes the fibrin-
to 8 were associated with increasing mortalities of 3.7, 7.2, and ogen levels were not predictive for coronary events during
12.6%, respectively. Patients seropositive to ⬎5 pathogens follow-up (16).
compared with those seropositive to ⬍4 pathogens had a 5.1 (iii) SAA. Serum amyloid A (SAA) is an acute-phase protein
higher risk of future cardiac death (86). Similar results are and apolipoprotein. In a cross-sectional study including men,
reported from a further study which included HAV in the participants with prevalent coronary heart disease had mark-
spectrum of pathogens (105). edly higher SAA levels than did participants without. The
associations weakened after further adjustment for central
obesity (45). In a prospective study in the general British male
population, baseline values of SAA were associated with future
risk of coronary heart disease. However, it was not investigated
Acute-phase reactants. One of the markers of inflammation whether this association was independent of possible con-
are the acute-phase proteins, which are, regulated by cyto- founders. No strong associations of SAA with H. pylori sero-
kines, produced in the liver. Further markers of inflammation positivity or C. pneumoniae IgG titers were observed (16, 18).
are decreased serum albumin levels and an increased leukocyte In patients with stable and unstable angina, no associations of
count. SAA concentrations with the risk of coronary events were
(i) CRP. C-reactive protein (CRP), a major acute-phase detected (16, 36). Again, the role of SAA as a risk factor for
protein, is a marker of systemic inflammation. CRP induces the the development of arteriosclerosis is uncertain, and further
expression of cell adhesion molecule in human endothelial studies are needed to determine whether this association is
cells and thus may play a direct role in promoting the inflam- independent of possible confounders.
matory component of arteriosclerosis (78). It has been shown (iv) Albumin. During inflammation, the concentration of
that the CRP concentration correlates with the presence and albumin in serum may decrease by up to 20%. Some studies
severity of coronary arteriosclerosis and the risk for acute indicate that patients with lower albumin levels have a higher
cardiovascular events (36, 48, 55, 69). Levels of CRP in serum risk for developing arteriosclerosis (18).
were higher in patients with unstable angina than in patients (v) Leukocyte count. Elevated leukocyte levels may lead to
with stable angina (12). During follow-up, however, CRP levels arteriosclerotic events either by an effect on chronic inflamma-
were not predictive for coronary events in patients with acute tion or by inducing acute thrombotic events. A relative eleva-
coronary syndromes (16). tion in leukocyte count was found to be associated with carotid
In a cross-sectional study including men, participants with arteriosclerosis, but this relationship differed by race ethnicity,
prevalent coronary heart disease had markedly higher CRP being strongest in Hispanics, intermediate in black non-His-
levels than did participants without coronary heart disease. panics, and not present in white non-Hispanics (22). In a study
The associations weakened after further adjustment for central of patients with stable angina pectoris, the leukocyte count was
obesity (45). an independent predictor of cardiovascular death, nonfatal
Controversial results are available for the association of el- myocardial infarction, and the risk of revascularization (37). A
evated CRP levels with serologic indicators of bacterial or viral further study, investigating the leukocyte count at baseline and

the development of coronary heart disease, did not find an Women without coronary artery disease but with atheroscle-
association between leukocyte count and development of cor- rotic risk factors (diabetes or hypertension) had significantly
onary heart disease (18). The percentage of aggregated leuko- elevated levels of total complement in serum compared with a
cytes in patients with unstable angina is significantly increased control group. The complement levels were highest in women
compared to that of patients with no evidence of active coro- with a combination of diabetes and hypertension (60).
nary artery disease (54). This aggregation may be mediated by (b) Complement C3. The levels of complement C3 in serum
cellular adhesion molecules (CAMs). in patients with coronary artery disease were higher than those
Indicators of activation of the immune system. (i) Lympho- in healthy controls (97). Women without coronary artery dis-
cytes. T lymphocytes are found in large numbers of human ease but with atherosclerotic risk factors (diabetes or hyper-
atherosclerotic plaques, indicating that immune and inflamma- tension) had significantly elevated levels of complement C3
tory mechanisms are important factors in the pathogenesis of compared with a control group. These levels were most ele-
arteriosclerosis. Upon activation by target cells, T-helper lym- vated in women with a combination of diabetes and hyperten-
phocytes (predominantly CD4⫹ cells) secrete cytokines. In hu- sion (60).
man coronary atherectomy tissue, T-helper (CD4) cells pre- (v) Circulating immune complexes. Women without coro-
dominate over suppressor (CD8) cells and B lymphocytes (70). nary artery disease but with atherosclerotic risk factors (dia-
In vitro studies have shown that T lymphocytes from patients betes or hypertension) had significantly elevated levels of cir-
with unstable angina, but not those from patients with chronic culating immune complexes compared with a control group.
stable angina or normal control subjects, proliferated in re- These levels were most elevated in women with a combination
sponse to autologous proteins from coronary plaques and/or to of diabetes and hypertension (60).
oxidized low-density lipoproteins (13). (vi) Circulating antitissue antibodies. Women without cor-
Patients with ischemic heart disease show an increase in the onary artery disease but with atherosclerotic risk factors (dia-
level of circulating cytotoxic T lymphocytes compared to nor- betes or hypertension) had significantly elevated levels of cir-
mal control subjects (67). Peripheral blood lymphocytes of culating antitissue antibodies compared with a control group.
patients with unstable angina are immunologically activated Women with a combination of diabetes and hypertension had
the highest levels of antitissue antibodies (60).
and produce soluble factors which may allow their interaction
Cytokines. During inflammation, cytokines are produced by
with endothelial cells in areas of inflammation. Circulating
inflammatory cells in the damaged tissue. Cytokines are also
activated CD4 and CD8 lymphocytes are suggested to be in-
produced in fat tissue. Proinflammatory cytokines exert a num-
volved in the inflammatory reaction during episodes of unsta-
ber of important effects on vascular reactivity. At one end of
ble angina (76). The numbers of CD4⫹ and CD3⫹/DR⫹ cells
the spectrum, cytokines such as IL-1 may induce vascular pa-
were higher in patients with unstable angina than in patients
resis. At the other end of the spectrum, cytokines such as
with stable angina (12). In unstable angina, the percentage of
tumor necrosis factor can induce endothelial dysfunction and
double-positive CD3⫹/DR⫹ cells significantly increased at
impair vascular dilatation (92).
days 7 to 15 and returned to baseline levels at 6 months. The
(i) IFN-␥. The inflammatory cytokine IFN-␥ has been found
increment of circulating CD3⫹/DR⫹ cells was inversely related
to be increased in patients with unstable angina, suggesting
to the admission levels of CRP and was associated with a better that it is probably related to myocardial cell damage or to
outcome (12). plaque rupture and thrombus formation (66). Furthermore, it
(ii) Neopterin. Neopterin is a by-product of activated mac- has been shown that in patients with unstable angina pectoris,
rophage metabolism, and the levels of neopterin increase in monocytes are activated by IFN-␥ (56).
several systemic inflammatory and infectious diseases. In pa- (ii) MCP-1. Levels of the inflammatory cytokine monocyte
tients with unstable angina, those with elevated neopterin lev- chemotactic protein 1 (MCP-1) have been found to be in-
els were more likely to be diagnosed with a non-Q-wave acute creased in patients with unstable angina, suggesting that
myocardial infarction and were more likely to have more se- MCP-1 is probably related to myocardial cell damage or to
vere and extensive arteriosclerosis than were patients with low plaque rupture and thrombus formation (66).
neopterin levels (35). During follow-up, however, neopterin (iii) IL-2. Variable IL-2 receptor subtype expression occurs
levels were not predictive for coronary events in patients with in mononuclear leukocytes infiltrating chronic human ather-
acute coronary syndromes (16). oma (70). An increase in the percentage of IL-2 receptor-
(iii) IgA, IgE, IgG, and IgM. In patients with coronary artery positive T lymphocytes was found in culprit lesions of patients
disease, the levels of IgM, but not of IgA and IgG, in serum with acute coronary syndromes (99). Levels of IL-2 in serum
were higher than those in healthy controls (97). In patients were higher in patients with unstable angina than in patients
with unstable angina, IgM levels in serum were higher than in with stable angina (12). In unstable angina, the levels of IL-2 in
stable angina patients (12). In unstable angina, the levels of serum significantly increased at days 7 to 15 and returned to
IgM in serum significantly increased at days 7 to 15 and re- baseline levels at 6 months (12). The IL-2 level was increased
turned to baseline levels at 6 months (12). Furthermore, in in patients with acute ischemic syndrome and patients with
middle-aged men at increased risk of myocardial infarction, stable angina compared to healthy controls (67).
hypertriglyceridemia and low levels of high-density lipoprotein (iv) IL-6. The level of IL-6 was increased in patients with
cholesterol were associated with an increased risk of a coro- acute ischemic syndrome compared to patients with stable
nary endpoint only if the levels of IgA, IgE, and IgG were also angina and healthy controls (67). During follow-up, however,
elevated (50). IL-6 levels were not predictive for coronary events in patients
(iv) Serum complement. (a) Total serum complement. with acute coronary syndromes (16). A further study in pa-
VOL. 9, 2002 MINIREVIEWS 211

tients with coronary heart disease showed that in patients with (sICAM-1), sVCAM-1, endothelial selectin, and platelet selec-
elevated IL-6 levels, CMV seropositivity was independently tin were elevated at presentation, remained elevated for 6
associated with a 3.2-fold increase in risk of future cardiac months compared to healthy controls, and decreased over the
death, whereas in individuals without IL-6 elevation, a previ- following 6 months (74, 94). Whether CAMs have a clinical
ous CMV infection had no effect on cardiac mortality (9). value in determining cardiovascular risk is at present uncer-
Indicators of autoimmunity. It has become apparent that tain. One study showed that in the prediction of coronary heart
the immune system is actively involved in the process that disease sICAM-1 is unlikely to add much predictive informa-
governs the progression of both early and the mature arterio- tion to that provided by more established risk factors (59). A
sclerotic plaques. Autoimmune mechanisms have been shown further study, however, showed that platelet selectin levels are
to take part in driving an inflammatory state within the ather- elevated among apparently healthy women at risk for future
oma. Among the candidate autoantigens dominating these vascular events (81).
processes are the Hsps, oxidized low-density lipoproteins, and
endothelial cell-bound antigens. VACCINATION AND ARTERIOSCLEROSIS
(i) Antibodies to Hsps. Hsps protect other proteins from It has been suggested that acute respiratory infection may be
denaturation and are produced after injuries involving heat, a risk factor for myocardial infarction and hypothesized that
infections, mechanical stress, oxidants, and cytokine stimula- influenza vaccine might reduce the risk of recurrent myocar-
tion. Cells of the arterial wall have been found to produce high dial infarction. A case-control study in patients with coronary
levels of Hsp when exposed to these stress factors. However, heart disease found that vaccination against influenza was neg-
Hsps bear the risk of autoimmunity because of their high atively associated with the development of myocardial infarc-
amino acid sequence homology between different species from tion during the same influenza season (75). On the other hand,
prokaryotes to humans. “Antigenic mimicry” may be caused by it has been hypothesized that vaccination may promote ath-
an immunological cross-reaction between microorganisms and erosclerosis by immunostimulation (53). Vaccination, particu-
autoantigens and thus may play an important role in the pro- larly with heat-inactivated bacteria, may contribute to the de-
cess of vascular endothelial injury (65). It has been suggested velopment of anti-Hsp antibodies (65).
that the immune response to Hsp60 or Hsp65 may be a link
between exposure to microorganisms and increased cardiovas- ENDOTHELIAL DYSFUNCTION, INFECTION, AND
cular risk. In a prospective population-based study, antibodies INFLAMMATION
to mycobacterial Hsp65 in serum were correlated with sero- The endothelium plays an important role in regulating vas-
positivity to C. pneumoniae and H. pylori (64). cular blood flow, and it is now apparent that endothelial dys-
The antibody titers to mycobacterial Hsp65 or Hsp60 were function is an important contributor to the pathogenesis of
strongly associated with carotid and coronary arteriosclerosis arteriosclerosis. Recently, infection and inflammation have
(8, 102, 103, 108). In a case-control study in patients undergo- been linked to endothelial dysfunction (6). The mechanisms by
ing coronary angiography, the simultaneous presence of anti- which inflammation may induce endothelial dysfunction are
bodies to C. pneumoniae and high levels of antibodies to hu- not fully understood. Cytokines have been identified to play a
man Hsp60 were found to be associated with coronary heart role in this process (7, 40). In men with coronary heart disease
disease (11). it has been shown that CRP concentration, CD8 lymphocytes
(ii) Antibodies to oxidized low-density lipoprotein. Oxida- expressing ICAM-1, and antibodies to oxidized low-density
tion of low-density lipoprotein occurs in the atherosclerotic lipoprotein were determinants of endothelium-dependent vas-
plaque and induces generation of antibodies to oxidized low- cular dysfunction (92).
density lipoprotein. These antibodies have been linked to risk
for myocardial infarction, especially in patients with diabetes
mellitus (57, 80).
(iii) AECA. After percutaneous transluminal coronary an-
gioplasty, anti-endothelial cell antibody (AECA)-positive pa- Statins. Large-scale clinical trials demonstrated significant
tients have been shown to have a higher rate of restenoses than reductions in cardiovascular event rates with statin therapy.
do AECA-negative patients (28). However, among chest pain The observed benefit of statin therapy, however, was larger in
patients, those with no coronary artery disease had levels of these trials than that expected on the basis of lipid lowering
AECA that did not differ from those in patients with coronary alone. Emerging evidence from both clinical trials and basic
artery disease (31). science studies suggests that statins have anti-inflammatory
(v) CAMs. The adhesion and transendothelial migration of properties, which may also lead to clinical efficacy. Statin ther-
leukocytes is thought to be important in the pathogenesis of apy reduced the level of CRP independently of its effect on
arteriosclerosis. These processes are mediated largely by lipid levels (1, 45, 49, 84). Thus, statin therapy might be effec-
CAMs. Upon histological analysis, human atherosclerotic tive in the primary prevention of coronary events among sub-
plaques contain many CAMs. CRP induces the expression of jects with relatively low lipid levels but with elevated levels of
CAMs in human endothelial cells (78). Patients with coronary CRP. Again, this hypothesis needs to be verified in large pro-
heart disease were shown to have higher soluble vascular cel- spective trials, which are currently under way.
lular adhesion molecule 1 (sVCAM-1) and endothelial selectin Antibiotics. If infection is the cause of arteriosclerosis, treat-
levels than do patients with normal coronary arteries (90). In ment with antibiotics should theoretically result in preventing
patients presenting with unstable angina and non-Q-wave in- some of the clinical manifestations of coronary and cerebro-
farction, the levels of soluble intercellular adhesion molecule 1 vascular arteriosclerosis. In investigating the relationship be-

TABLE 1. Published trials of antibiotics used for secondary prevention of coronary artery disease events
Study by:
Gupta et al. (33) Gurfinkel et al. (34) Muhlestein et al. (72)

Yr published 1997 1999 2000

Treatment duration 6 days 30 days 3 mo
No. of patients 80 202 302
Enrollment statusc Stable CAD, IgG ⬎ 1:64 Unstable angina Stable CAD, IgG ⬎ 1:16
Follow-up period (mo) 18 6 24

Cardiovascular mortality
% Active NGd 2.2 3.3
% Placebo NG 5.2 2.6

Cardiac eventsa
% Active 8 8.7 14.6
% Placebo 28 14.6 16.4
Sum of cardiovascular mortality, nonfatal myocardial infarction, admission for unstable angina pectoris, or unplanned revascularization data.
AZITH, azithromycin; ROXIT, roxithromycin.
CAD, coronary artery disease.
NG, numbers not given in the publication.

tween prior antibiotic use and cardiac events, a population- events in order to target the most intensive therapy to these
based case-control study found little or no association between patients. Measurement of markers of myocyte necrosis, such as
use of macrolide or tetracyclin antibiotics during the previous creatine kinase MB, myoglobin, and troponin I, are only par-
5 years and the risk of first myocardial infarction (44). Expo- tially successful in risk stratification. Recently, it has been
sures to short courses of antibiotics during the previous 2 years shown, that pregnancy-associated plasma protein A (PAPP-A),
were not associated with a lower risk of ischemic stroke in a potentially proarteriosclerotic metalloproteinase, is present
patients aged 65 years and older (58). Long-term azithromycin in unstable coronary plaques and that circulating levels are
treatment did not affect levels of the adhesion molecules in elevated in acute coronary syndromes. Thus, PAPP-A is a new
plasma over a period of 6 months (90). In a small study of candidate marker of unstable angina and acute myocardial
patients after percutaneous coronary angioplasty with con- infarction (3).
firmed H. pylori infection, eradication therapy with clarithro-
mycin, amoxycillin, and omeprazole for 1 week significantly CONCLUSION
attenuated reduction of the coronary artery lumen (51).
Up to now, three treatment trials with antibiotics for sec- Arteriosclerosis is a multifactorial disease. Traditional risk
ondary prevention of coronary artery disease events in humans factors are associated with arteriosclerosis in a significant num-
have been carried out (see Table 1) (33, 34, 72). To our knowl- ber of patients. According to current knowledge, there is only
edge, no trials regarding antibiotics for secondary prevention a weak association between infection and the precipitation or
of stroke in humans have been published. A further study, acute manifestations of arteriosclerosis. The study results are
published only as an abstract, in patients with acute coronary very contradictory, mainly due to methodological causes. Ad-
syndrome found that a 1-week therapy of either azithromycin ditionally, many studies have included only male patients, thus
plus metronidazole or amoxicillin plus metronidazole lead to a leaving open the question as to whether the results are appli-
better clinical outcome within 1 year than did a placebo cable to both genders. Further prospective large investigations
(A. F. M. Stone, M. Mendall, J. C. Kaski, S. Gupta, J. Camm, need to be conducted to study the association of infection with
and T. Northfield, Abstr., J. Am. Coll. Cardiol. 37:349A, 2001). the pathogenesis of arteriosclerosis. If the infectious pathogens
Further trials are under way to investigate the impact of a associated with arteriosclerosis are clearly demonstrated, large
3-month (21) or 1-year (43) course of azithromycin on the studies can be designed to assess the efficacy of antibiotics in a
progression of coronary heart disease in patients with prior selected group of patients in whom infection is the major
myocardial infarction. According to current knowledge, there underlying cause. Furthermore, the anti-inflammatory role of
are no indications to use antibiotics for secondary prevention other drugs, such as statins, and their benefit in primary and
of arteriosclerosis, except within well-designed randomized secondary prophylaxis of arteriosclerosis needs to be evalu-
clinical trials. Furthermore, prolonged use of antibiotics in a ated. In the meantime, we should concentrate on the “old-
large population may result in antibacterial resistance, which is fashioned” risk factors for arteriosclerosis, encouraging pa-
a major public concern, especially since the relationship be- tients to stop smoking and to treat their elevated blood
tween infection and arteriosclerosis is far from proven. pressure, blood glucose, and lipid levels.
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